Receptors & Clinical Investigation (E-Journal - Smart Science & Technology)
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Uncovering unique roles of LPA receptors in the tumor microenvironment
Get PDFThe role of the lysophospholipase D autotaxin (ATX) and lysophosphatidic acid (LPA) in cancer is emerging and represents two key players in regulating cancer progression. In this brief review, we will discuss some of our recent findings, which highlight a central role that LPA and its receptor plays in orchestrating melanoma-stroma interactions in the establishment of lung metastases. In particular, we evaluated not only the function of LPA receptors on tumor cells but also their role on host tissues and how they can influence melanoma growth and metastasis. Using the syngeneic B16F10 murine melanoma model, we made three key observations. First, our in vitro findings demonstrate that LPA receptors, specifically LPA2 and LPA5 expressed in B16F10 cells appear to have opposing roles in cell invasion; the former seems to be responsible for the high basal invasion rate of B16F10 cells while the latter is anti-invasive upon exogenous LPA stimulation. Second, we observed a profound reduction in the incidence of pulmonary melanoma metastasis in LPA1- and LPA5-knockout (KO) mice, respectively, when compared to wild-type (WT) mice. Third, no differences in terms of subcutaneous tumor growth between LPA1KO, LPA5KO and WT mice were observed. These findings suggest that LPA receptors exert different functions in melanoma cells versus host tissues in terms of invasion and metastasis
From bony fishes to mammals: reproductive cycles in vertebrates, hormones and hormone-receptors
Get PDFSome reproductive cycles of vertebrates are still little known. Yet, a good knowledge of reproductive cycles and regulation is useful to protect a threatened species, or inversely to control the proliferation of a species which has been recognized as a pest, or still when an animal becomes a model used to study fundamental physiological phenomena with applications to medical research. So, for several years, the studies of our laboratory and associated teams were devoted to the study of reproduction in several vertebrates, related to the external conditions which can be natural (climate, genetics) as well as artificial (pollution). In a first time, variations of both male and female genital tracts were studied in several vertebrates with anatomical and histological methods. To-day, the availability of a large panel of antibodies directed against hormones and their receptors allows the visualization of such molecules in organs according to sexual cycles or submitted to artificial factors such as pollution. Sexual cycles and the importance of hormones and their receptors in regulation are now an important purpose for our own works. Vertebrate models studied to-day are bony fishes living in fresh water, amphibians, reptiles and mammals, living in semi-aquatic, temperate, equatorial, Mediterranean or arid climates. Our purpose is to obtain a large panel of situations allowing the understanding of the complexity and plasticity of reproductive modes, and the effects of external factors of animal species in order to be useful to the preservation of threatened species, regulation of reproduction on animals considered as pests and use of animal models
Fibrosis: a novel approach for an old problem
Get PDFDupuytren’s disease is a fibroproliferative disease of the hand palm that results in permanent finger flexion and is the most common inherited condition to affect the body’s connective tissue with a global presence of 3-6%. It was originally known as the Viking’s disease and thought to be originated in the seventh or early eight century AD. In 1832 Baron Guillaume Dupuytren named and gave the first anatomo-clinical description of the disease. To date the causes underlying Dupuytren’s disease are unknown and surgery remains the standard of care. Multiple recurrences are a common feature of this disease, following surgical removal of the primary fibrotic formations. Our research focuses on understanding of the molecular mechanisms that are at the basis of the progression of fibrosis. In our recently published manuscript we described how modulation of the TGF? signaling pathway results in “reduction” of the fibrotic content of the disease. Dupuytren’s resection specimens can now be maintained ex vivo providing a suitable model for preclinical screening of different classes of potential antifibrotic drugs; antisense oligonucleotides, chemical inhibitors, and miRNA- based therapies. Our findings indicate that decrease of collagen deposition, which is pathological characteristic of Dupuytren’s, can be achieved by blocking the main regulatory pathway of collagen expression and remodeling. Short term gene expression modulation could have prolonged antifibrotic effects, even upon withdrawal of the modulatory factor (e.g. pharmacological inhibitor). Dupuytren’s field of research is shifting direction from symptom-oriented studies towards molecular pathogenesis and gene expression “correction” attempts. Future studies shall focus on the molecular, epigenetic or immune modulation of key fibrotic stimuli in combination with current treatments with ultimate goal, to not only relief the primary symptoms, but mainly to prevent recurrence of the disease. Here, we discuss the applicability of ex vivo screening of potential pre-drugs on Dupuytren’s-derived tissue for the treatment of various fibrotic diseases
EphB and ephrinB in pain signaling
Get PDFThe Ephrin type B receptors (EphB) and their membrane bound ephrinB ligands are involved in diverse facets of cell physiology and pathophysiology. EphB-ephrinB signaling mediates synapse formation and plasticity by regulating the insertion, localization and function of glutamate receptors in synaptic membranes. Whereas, EphB-ephrinB signaling at the excitatory glutamatergic synapses in the dorsal horns of the spinal cord, has been implicated in the pathophysiology of pain. Here, the key evidence that support the participation of EphB-ephrinB signaling in pain processes are highlighted. Then, a possible role for the pseudokinase EphB6 in the EphB-ephrinB pain signaling complex is considered. These pathways are currently being intensely studied to exploit selective therapeutic targets for pain relief
Estrogen receptor-? signaling and localization regulates autophagy and unfolded protein response activation in ER+ breast cancer
Get PDFAntiestrogen therapy is commonly used to treat estrogen receptor (ER)+ breast cancers but acquired and de novo resistance limits their overall curative potential. An endoplasmic reticulum stress pathway, the unfolded protein response, and autophagy are both implicated in the development of antiestrogen therapy resistance in estrogen receptor-? (ER) positive breast cancer. Thus, we recently investigated how ER? can regulate autophagy and the unfolded protein response (Cook et al., FASEBJ, 2014). We showed that inhibiting ER? signaling stimulates autophagosome formation and flux. Moreover, we showed that ER? knockdown inhibited the unfolded protein response (UPR) signaling components. Here we support and extend this recent report showing additional data on ER? localization and provide a schematic of the overall signaling implicated by our results. Differential activation of UPR and autophagy highlight the pivotal role of ER? in regulating pro-survival signaling in breast cancer through UPR and autophagy. Furthermore, these data suggest new approaches to successful targeting ER? and preventing the regulation of key pro-survival signaling that confers resistance to endocrine therapies. 
Protein S-sulfhydration as a major sources of H2S bioactivity
Get PDFThe physiological and biomedical importance of hydrogen sulfide (H2S) has been extensively studied in our body. H2S can be endogenously produced in a variety of cells and tissues by cystathionine ?-lyase, cystathionine ?-synthase, and/or 3-mercaptopyruvate sulfurtransferase, and is involved in the regulation of vascular function, cell growth, insulin secretion, neurotransmission, myocardial contractility, inflammation, and nociception, etc. H2S post-translationally modifies proteins by yielding a hydropersulfide moiety (–SSH) in specific cysteine residue(s), termed as S-sulfhydration. It is becoming increasingly recognized that S-sulfhydration is a major sources of H2S bioactivity. In this research highlight, we discuss our latest published findings which demonstrate the S-sulfhydration regulation of proteins by H2S and their importance in aging and cancer protection
FARNESOID X RECEPTOR AND REPRODUCTION
Get PDFFarnesoid X alpha receptors (FXR? or NR1H4) are present in male and female reproductive tissues. The aim of the present review is to describe those actions of the most relevant ligands of FXR? on reproduction and the interaction of this receptor with other nuclear receptors, for understanding the possible role of FXR? in reproductive events. Thus, although the relevance of the FXR? on reproduction is widely unknown, its endogenous ligands like farnesol, chenodeoxycholic acid (CDCA), and cholate acid (CA) participate in proliferation, apoptosis, differentiation, and steroidogenesis in reproductive tissues. In these tissues FXR? modulates estrogen and androgen actions. Since FXR? is stretched related to other nuclear receptors, also present in reproductive tissues, such as the liver X receptors (LXR), peroxisome proliferation-activated receptor (PPAR), liver receptors homolog-1 (LRH-1), small heterodimer partner (SHP), and dosage-sensitive sex reversal (DAX1), the FXR? actions on reproductive tissues might be directly or indirectly mediated by its interaction with these nuclear receptors
Interaction of nicotinic receptors with bupropion: Structural, functional, and pre-clinical perspectives
Get PDFBesides the antidepressant activity of bupropion (BP), preclinical studies in rodents provide evidence that this compound and its hydroxyl metabolites can attenuate nicotine withdrawal, reversing both the physical and negative affective aspects of nicotine abstinence. Co-interactions of BP with nicotine or other psychostimulants influence decrease anxiety- and cognitive- related processes. BP also attenuates the reinstatement of nicotine-induced conditioned place preference in rats caused by a priming dose of nicotine, morphine, cannabinoids, or ethanol. Therefore, BP can offer an interesting approach to the prevention of relapse in humans. There is emerging evidence that BP inhibits, in the low to intermediate micromolar range, various nicotinic acetylcholine receptors (AChRs) expressed in different neuronal pathways. The BP selectivity for different AChRs follows the sequence: ?3- > ?4- ~ ?1- > ?7-containing AChRs. This receptor blockade may contribute to its dual therapeutic activity as either an antidepressant or anti-nicotinic drug. Regarding the structural aspects, two distinct binding sites for [125I]SADU-3-72, a photosensitive derivative of BP, were identified in the Torpedo AChR. A binding site is located within the ion channel, which coincides with the molecular docking results, whereas a second site is found near the extracellular end of ?1-M1 when the receptor is in the desensitized state. Interestingly, BP greatly reduces the potentiating action elicited by Zn2+ on different non-?7 AChRs, and vice versa this cation increases the inhibitory strength of BP. This contrasting behavior supports the concept that the binding sites for BP and Zn2+are located at different domains. The understanding of the BP activity, alone or in combination with other drugs (e.g., nicotine), at the molecular and behavioral levels, may improve the knowledge of the underlying mechanisms of action. This knowledge is essential for the development of novel BP (or other antidepressant) derivatives with improved clinical profiles for the treatment of depression and psychostimulant-related addictions
A new specific neuronal modulatory effect of nicotine: the functional cross talk between nicotinic and glutamate receptors
Get PDFWe here have addressed the topic of the cross-talk between receptors. We provide evidence supporting the co-localization and the functional interaction between nicotinic acetylcholine receptors and some glutamatergic receptors. The recruitment of nicotinic acetylcholine receptors dynamically and negatively modulates the function of both N-methyl-D-aspartic acid (NMDA) and ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors throughout their selective internalization. This dynamic control by cholinergic nicotinic system of NMDA and ?-AMPA receptors is operative even at very low concentrations of nicotine. Nicotinic and glutamatergic receptors have been both implicated in important neurological and psychiatric disorders such as Alzheimer’s and Parkinson’s disease, schizophrenia, and anxiety. Thus, a more extensive and detailed knowledge of this new modulatory role of nicotine may eventually enable us to develop specific therapeutic interventions for these pathologies
The Dynamic Dyad: Cardiac Ryanodine Receptors on the Move
Get PDFThis research highlight focuses on new developments in our understanding of the structure and function of the mammalian dyad, and of the type 2 ryanodine receptor (RyR2) in particular. Recent investigations have challenged the view of dyads as static and repetitive structures with one functioning much as the next. New data has revealed that dyads have diverse molecular architectures and are dynamic structures where the organization of their RyR2 can be changed by changes in the local environment